Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450052, Henan, China.
Department of Nuclear Medicine, Xinxiang Central Hospital, Xinxiang, 453002, Henan, China.
Br J Cancer. 2024 May;130(11):1770-1782. doi: 10.1038/s41416-024-02683-x. Epub 2024 Apr 10.
Tumour-associated macrophages (TAMs) are an important component of the tumour microenvironment (TME). However, the crosstalk between oesophageal squamous cell carcinoma (ESCC) cells and TAMs remains largely unexplored.
Clinical samples and the TCGA database were used to evaluate the relevance of SPP1 and TAM infiltration in ESCC. Mouse models were constructed to investigate the roles of macrophages educated by SPP1 in ESCC. Macrophage phenotypes were determined using qRT‒PCR and immunohistochemical staining. RNA sequencing was performed to elucidate the mechanism.
Increasing expression of SPP1 correlated with M2-like TAM accumulation in ESCC, and they both predicted poor prognosis in the ESCC cohort. Knockdown of SPP1 significantly inhibited the infiltration of M2 TAMs in xenograft tumours. In vivo mouse model experiments showed that SPP1-mediated education of macrophages plays an essential role in the progression of ESCC. Mechanistically, SPP1 recruited macrophages and promoted M2 polarisation via CD44/PI3K/AKT signalling activation and then induced VEGFA and IL6 secretion to sustain ESCC progression. Finally, blockade of SPP1 with RNA aptamer significantly inhibited tumour growth and M2 TAM infiltration in xenograft mouse models.
This study highlights SPP1-mediated crosstalk between ESCC cells and TAMs in ESCC. SPP1 could serve as a potential target in ESCC therapy.
肿瘤相关巨噬细胞（TAMs）是肿瘤微环境（TME）的重要组成部分。然而，食管鳞状细胞癌（ESCC）细胞与 TAMs 之间的串扰在很大程度上仍未得到探索。
使用临床样本和 TCGA 数据库评估 SPP1 和 TAM 浸润在 ESCC 中的相关性。构建小鼠模型以研究由 SPP1 教育的巨噬细胞在 ESCC 中的作用。使用 qRT-PCR 和免疫组织化学染色来确定巨噬细胞表型。进行 RNA 测序以阐明机制。
SPP1 表达增加与 ESCC 中 M2 样 TAM 积累相关，并且它们都在 ESCC 队列中预测预后不良。SPP1 的敲低显著抑制了异种移植肿瘤中 M2 TAM 的浸润。体内小鼠模型实验表明，SPP1 介导的巨噬细胞教育在 ESCC 的进展中起着至关重要的作用。从机制上讲，SPP1 通过 CD44/PI3K/AKT 信号通路的激活招募巨噬细胞并促进 M2 极化，然后诱导 VEGFA 和 IL6 的分泌以维持 ESCC 的进展。最后，用 RNA 适体阻断 SPP1 可显著抑制异种移植小鼠模型中的肿瘤生长和 M2 TAM 浸润。
这项研究强调了 SPP1 在 ESCC 中在 ESCC 细胞与 TAMs 之间的串扰。SPP1 可作为 ESCC 治疗的潜在靶点。
